EP2269591A2 - Verbesserte pharmazeutische Zusammensetzungen - Google Patents

Verbesserte pharmazeutische Zusammensetzungen Download PDF

Info

Publication number
EP2269591A2
EP2269591A2 EP10177365A EP10177365A EP2269591A2 EP 2269591 A2 EP2269591 A2 EP 2269591A2 EP 10177365 A EP10177365 A EP 10177365A EP 10177365 A EP10177365 A EP 10177365A EP 2269591 A2 EP2269591 A2 EP 2269591A2
Authority
EP
European Patent Office
Prior art keywords
amino
ritonavir
hydroxy
weight
amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP10177365A
Other languages
English (en)
French (fr)
Other versions
EP2269591A3 (de
EP2269591B1 (de
Inventor
Laman Alani
Soumojeet Ghosh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Inc
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23936923&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP2269591(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to SI200031095T priority Critical patent/SI2269591T1/en
Publication of EP2269591A2 publication Critical patent/EP2269591A2/de
Publication of EP2269591A3 publication Critical patent/EP2269591A3/de
Application granted granted Critical
Publication of EP2269591B1 publication Critical patent/EP2269591B1/de
Anticipated expiration legal-status Critical
Revoked legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to improved pharmaceutical formulations comprising at least one HIV protease inhibiting compound in a pharmaceutically acceptable solution of a medium and/or long chain fatty acid, ethanol or propylene glycol, and water, wherein said HIV protease inhibiting compound contained therein has improved solubility properties.
  • HIV protease inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years.
  • a particularly effective HIV protease inhibitor is (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)-methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl) -amino)-1,6-diphenyl-3-hydroxyhexane(ritonavir), which is marketed as NORVIR ® .
  • Ritonavir is known to have utility for the inhibition of HIV protease, the inhibition of HIV infection, and the enhancement of the pharmacokinetics of compounds which are metabolized by cytochrome P 450 monooxygenase.
  • Ritonavir is particularly effective for the inhibition of HIV infection when used alone or in combination with one or more reverse transcriptase inhibitors and/or one or more other HIV protease inhibitors.
  • HIV protease inhibiting compounds typically are characterized by having poor oral bioavailability, and there is a continuing need for the development of improved oral dosage forms for HIV protease inhibitors having suitable oral bioavailability, stability, and side effects profiles.
  • compositions comprising ritonavir or a pharmaceutically acceptable salt thereof are disclosed in U.S. Patent Nos. 5,541,206, issued July 30, 1996 ; 5,484,801, issued January 16, 1996 ; 5,725,878, issued March 10, 1998 ; and 5,559,158, issued September 24, 1996 and in International Application No. WO98/22106, published May 28, 1998 (corresponding to U.S. Serial No. 08/966,495, filed November 7, 1997 ), the disclosures of all of which are herein incorporated by reference.
  • HIV protease inhibiting compounds include: N-(2(R)-hydroxy-1 (S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-p entaneamide (for example, indinavir) and related compounds, disclosed in European Patent Application No. EP 541168, published May 12, 1993 , and U.S. Patent No.
  • EP532466 published March 17, 1993 , which is incorporated herein by reference; 1 -Naphthoxyacetyl-beta- methylthio-Ala-(2S,3S) -3-amino-2-hydroxy-4-butanoyl 1,3--thiazolidine-4-t-butylamide (for example, 1-Naphthoxyacetyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBu), 5-isoquinolinoxyacetyl-beta- ⁇ nethylthio-Ala-(2S,3S)-3-amino -2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide , and related compounds, disclosed in European Patent Application No.
  • W093/23368 published November 25, 1993 , both of which are herein incorporated by reference; (for example, VX-478) and related compounds, disclosed in PCT Patent Application No. W0 94/05639, published March 17, 1994 , which is incorporated herein by reference; (for example, DMP-323) or (for example, DMP-450) and related compounds, disclosed in PCT Patent Application No. W0 93/07128, published April 15, 1993 , which is incorporated herein by reference; (for example, AG1343, (nelfinavir)), disclosed in PCT Patent Application No. W0 95/09843, published April 13, 1995 and U.S. Patent No.
  • EP560268 published September 15, 1993 , which is incorporated herein by reference; and (for example, U-140690 (tipranavir)) and related compounds disclosed in PCT Patent Application No. WO 9530670, published November 16, 1995 , and U.S. Patent No. 5,852,195, issued December 22, 1998 , the disclosures of both of which are herein incorporated by reference; or a pharmaceutically acceptable salt of any of the above.
  • HIV protease inhibiting compound includes a compound of formula I: or a pharmaceutically acceptable salt thereof, disclosed in PCT Patent Application No. W0 94/14436, published July 7, 1994 , and U.S. Patent No. 5,541,206, issued July 30, 1996 , the disclosures of both of which are herein incorporated by reference.
  • the compounds of formula I are useful to inhibit HIV infections and, thus, are useful for the treatment of AIDS.
  • HIV protease inhibiting compound is a compound of formula II: and related compounds, or a pharmaceutically-acceptable salt thereof, as disclosed in U.S. Patent Application No. 08/572,226, filed December 13, 1996 and U.S. Patent Application No. 08/753,201, filed November 21, 1996 , and International Patent Application No. WO 97/21685, published June 19, 1997 , the disclosures of which are herein incorporated by reference.
  • a preferred compound of formula II is known as ABT-378 and has a chemical name of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2S- (1-tetrahydropyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane, or a pharmaceutically-acceptable salt thereof.
  • the preparation of this compound is disclosed in U.S. Patent No. 5,914,332, issued June 22, 1999 , the disclosure of which is herein incorporated by reference.
  • Solubility is an important factor in the formulation of HIV protease inhibiting compounds.
  • Compounds of formula I typically have an aqueous solubility of approximately 6 micrograms per milliliter at pH >2. This is considered to be extremely poor aqueous solubility and, therefore, a compound of formula I in the free base form would be expected to provide very low oral bioavailability.
  • the free base form of a compound of formula I, administered as an unformulated solid in a capsule dosage form is characterized by a bioavailability of less than 2% following a 5 mg/kg oral dose in dogs.
  • the bis-tosylate of a compound of formula I administered as an unformulated solid in a capsule dosage form, is characterized by a bioavailability of less than 2% following a 5 mg/kg oral dose in dogs.
  • the oral bioavailability of a compound of formula I should be at least 20%.
  • the oral bioavailability of a compound of formula I from the dosage form should be greater than about 40% and, more preferably, greater than about 50%.
  • One measure of the potential usefulness of an oral dosage form of a pharmaceutical agent is the bioavailability observed after oral administration of the dosage form.
  • Various factors can affect the bioavailability of a drug when administered orally. These factors include aqueous solubility, drug absorption, dosage strength and first pass effect.
  • Aqueous solubility is one of the most important of these factors.
  • a drug has poor aqueous solubility, attempts are often made to identify salts or other derivatives of the drug which have improved aqueous solubility.
  • a salt or other derivative of the drug is identified which has good aqueous solubility, it is generally accepted that an aqueous solution formulation of this salt or derivative will provide the optimum oral bioavailability.
  • the bioavailability of the oral solution formulation of a drug is then generally used as the standard bioavailability against which other oral dosage forms can be measured.
  • compositions of the instant invention provide greatly improved solubility for said solubilized HIV protease inhibiting compounds contained therein when compared to analogous compositions without the addition of water.
  • a preferred composition of the invention is a solution comprising (a) a solubilized HIV protease inhibiting compound or a combination of solubilized HIV protease inhibiting compounds (preferably, a compound of the formula I or II, or saquinavir or nelfinavir or indinavir or, more preferably, ritonavir or ABT-378 or saquinavir or nelfinavir or indinavir, or, most preferably, ritonavir or ABT-378); or a combination of ritonavir or nelfinavir and another HIV protease inhibitor (preferably, ABT-378 or saquinavir or indinavir or nelfinavir, or, more preferably, a combination of ritonavir or nelfinavir and another HIV protease inhibitor (preferably, ABT-378 or saquinavir or indinavir or nelfinavir), or, most preferably,
  • a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable medium and/or long chain fatty acid or mixtures thereof in the amount of from about 20% to about 99% (preferably, from about 30% to about 75% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable medium and/or long chain fatty acid or mixtures thereof in the amount of from about 20% to about 99% (preferably, from about 30% to about 75% by weight of the total solution; (2) ethanol in the amount of from about 1% to about 15% (preferably, from about 3% to about 12%) by weight of the total solution, or, alternatively, propylene glycol in the amount of from about 1% to about 15% (preferably, from about 5% to about 10%); (c) water in the amount of from about 0.4% to about 3.5%; and optionally, (d) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% (preferably, from about 2% to about 20% and most preferably, from about 2.5% to about 15%) by weight of the total solution.
  • preferred ratios (w/w) of ritonavir to ABT-378 are from about 1:16 to about 5:1. Even more preferred is a ratio of ritonavir to ABT-378 of from about 1:8 to about 3:1. An even more preferred ratio of ritonavir to ABT-378 is 1:4.
  • micellar solutions as described herein may include micellar solutions, which are thermodynamically stable systems formed spontaneously in water above a critical temperature and concentration. Said micellar solutions contain small colloidal aggregates (micelles), the molecules of which are in rapid thermodynamic equilibrium with a measurable concentration of monomers. Micellar solutions exhibit solubilization phenomena and thermodynamic stability.
  • micellar solutions which are thermodynamically stable systems formed spontaneously in water above a critical temperature and concentration.
  • Said micellar solutions contain small colloidal aggregates (micelles), the molecules of which are in rapid thermodynamic equilibrium with a measurable concentration of monomers. Micellar solutions exhibit solubilization phenomena and thermodynamic stability.
  • pharmaceutically acceptable alcohol refers to alcohols which are liquid at room temperature, for example ethanol, propylene glycol, 2-2(ethoxyethoxy) ethanol (Transcutol ® , Gattefosse, Westwood, NJ), benzyl alcohol, glycerol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and the like, or mixtures thereof.
  • a more preferred composition of the invention is a solution comprising (a) solubilized ritonavir in the amount of from about 1% to about 30% (preferably, from about 5% to about 25%) by weight of the total solution, (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable medium and/or long chain fatty acid in the amount of from about 40% to about 99% (preferably, from about 30% to about 75% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 99% (preferably, from about 30% to about 75% by weight of the total solution and (2) ethanol in the amount of from about 1% to about 15% (preferably, from about 3% to about 12%) by weight of the total solution, (c) water in the amount of from about 0.4% to about 3.5% and (d) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 20% (preferably, from about 2.5% to about 10%) by weight of the total solution
  • composition of the invention is a solution comprising (a) solubilized ritonavir in the amount of from about 1 % to about 30% (preferably, from about 5% to about 25%) by weight of the total solution, (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 15% to about 99% (preferably, from about 30% to about 75% by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 15% to about 99% (preferably, from about 30% to about 75% by weight of the total solution and (2) ethanol in the amount of from about 1% to about 15% (preferably, from about 3% to about 12%) by weight of the total solution, (c) water in the amount of from about 0.4% to about 3.5%, and (d) polyoxyl 35 castor oil in the amount of from about 0% to about 20% (preferably, from about 2.5% to about 10%) by weight of the total solution.
  • a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount
  • a most preferred composition of the invention is a solution comprising (a) solubilized ritonavir in the amount of about 10% by weight of the total solution, (b) a pharmaceutically acceptable organic solvent which comprises a mixture of (1) oleic acid in the amount of from about 70% to about 75% by weight of the total solution and (2) ethanol in the amount of from about 3% to about 12%, preferably, about 12%, by weight of the total solution, (c) water in the amount of from about 0.4% to about 1.5% and (d) polyoxyl 35 castor oil in the amount of about 6% by weight of the total solution.
  • the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of about 0.025% by weight of the total solution.
  • SEC soft elastic gelatin capsule
  • BHT butylated hydroxytoluene
  • a more preferred composition of the invention is a solution comprising (a) a combination of solubilized HIV protease inhibiting compounds which are ritonavir and ABT-378 in the amount of from about 1% to about 45% (preferably, from about 5% to about 45%) by weight of the total solution, and (b) a pharmaceutically acceptable organic solvent which comprises (i) a pharmaceutically acceptable medium and/or long chain fatty acid in the amount of from about 40% to about 99% (preferably, from about 30% to about 75% by weight of the total solution or (ii) a mixture of (1) a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 99% (preferably, from about 30% to about 75% by weight of the total solution and (2) propylene glycol in the amount of from about 1% to about 15% by weight of the total solution, (c) water in the amount of from about 0.4% to about 3.5% and (d) a pharmaceutically acceptable surfactant in the amount of from about 0% to about 20% (preferably,
  • the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.
  • SEC soft elastic gelatin capsule
  • composition of the invention is a solution comprising (a) a combination of solubilized HIV protease inhibiting compounds which are ritonavir and ABT-378 in the amount of from about 1% to about 45% (preferably, from about 5% to about 45%) by weight of the total solution, (b) a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 15% to about 99% (preferably, from about 30% to about 75% by weight of the total solution or (ii) a mixture of (1) oleic acid in the amount of from about 15% to about 99% (preferably, from about 30% to about 75% by weight of the total solution and (2) propylene glycol in the amount of from about 1% to about 8% by weight of the total solution, (c) water in the amount of from about 0.4% to about 3.5%, and (d) polyoxyl 35 castor oil in the amount of from about 0% to about 20% (preferably, from about 2.5% to about 10%) by weight of the total solution.
  • a pharmaceutically acceptable organic solvent
  • the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.
  • SEC soft elastic gelatin capsule
  • the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of about 0,025% by weight of the total solution.
  • SEC soft elastic gelatin capsule
  • BHT butylated hydroxytoluene
  • the amount of water employed in the pharmaceutical composition of the instant invention comprises from about 0.4% to about 3.5% by weight of the total solution of water.
  • the weight of the total solution of water is from about 0.4% to about 2.0%; more preferably from about 0.4% to about 1.5%; and the most preferred being about 1%.
  • composition of the invention can comprise antioxidants (for example, ascorbic acid, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, and the like) for chemical stability.
  • antioxidants for example, ascorbic acid, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, and the like
  • pharmaceutically acceptable acid refers to (i) an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, (ii) an organic mono-, di- or tri-carboxylic acid (for example, formic acid, acetic acid, adipic acid, alginic acid, citric acid, ascorbic acid, aspartic acid, benzoic acid, butyric acid, camphoric acid, gluconic acid, glucuronic acid, galactaronic acid, glutamic acid, heptanoic acid, hexanoic acid, fumaric acid, lactic acid, lactobionic acid, malonic acid, maleic acid, nicotinic acid, oxalic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, succinic acid, tartaric acid, undecanoic acid and the like) or (iii)
  • pharmaceutically acceptable surfactant refers to a pharmaceutically acceptable non-ionic surfactant for example, polyoxyethylene castor oil derivatives (for example, polyoxyethyleneglyceroltriricinoleate or polyoxyl ethylene 35 castor oil (Cremophor ® EL, BASF Corp.) or polyoxyethyleneglycerol oxystearate (Cremophor ® RH 40 (glycerol polyethyleneglycol oxystearate) or Cremaphor ® RH 60 (polyethyleneglycol 60 hydrogenated castor oil), BASF Corp., and the like) or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylenepolypropylene glycol, such as Poloxamer ® 124, Poloxamer ® 188, Poloxamer ® 237, Poloxamer ® 338, Poloxamer ® 407, and the like, (BASF Wy
  • a preferred pharmaceutically acceptable surfactant is polyoxyl 35 castor oil (Cremophor ® EL, BASF Corp.), polyoxyethylene (20) sorbitan monolaurate (Tween ® ) 20), polyoxyethylene (20) sorbitan monooleate (Tween ® 80) or a sorbitan fatty acid ester, for example sorbitan oleate.
  • a most preferred pharmaceutically acceptable surfactant is polyoxyl 35 castor oil (Cremophor ® EL, BASF Corp.).
  • the term "substantially pure”, when used in reference to a polymorph of ritonavir, refers to a polymorph of ritonavir, Form I or Form II, which is greater than about 90% pure. This means that the polymorph of ritonavir does not contain more than about 10% of any other compound and, in particular, does not contain more than about 10% of any other form of ritonavir. More preferably, the term “substantially pure” refers to a polymorph of ritonavir, Form I or Form II, which is greater than about 95% pure.
  • the polymorph of ritonavir does not contain more than about 5% of any other compound and, in particular, does not contain more than about 5% of any other form of ritonavir.
  • the term "substantially pure” refers to a polymorph of ritonavir, Form I or Form II, which is greater than about 97% pure. This means that the polymorph of ritonavir does not contain more than about 3% of any other compound and, in particular, does not contain more than about 3% of any other form of ritonavir.
  • the term “substantially pure”, when used in reference to amorphous ritonavir, refers to amorphous ritonavir which is greater than about 90% pure. This means that the amorphous ritonavir does not contain more than about 10% of any other compound and, in particular, does not contain more than about 10% of any other form of ritonavir. More preferably, the term “substantially pure”, when used in reference to amorphous ritonavir, refers to amorphous ritonavir, which is greater than about 95% pure.
  • the amorphous ritonavir does not contain more than about 5% of any other compound and, in particular, does not contain more than about 5% of any other form of ritonavir.
  • the composition and preparation of soft elastic gelatin capsules is well known in the art.
  • the composition of a soft elastic gelatin capsule typically comprises from about 30% to about 50% by weight of gelatin NF & EP, from about 20% to about 30% by weight of a plasticizer, and from about 25% to about 40% by weight of water.
  • Plasticizers useful in the preparation of soft elastic gelatin capsules are glycerin, sorbitol, or propylene glycol and the like, or combinations thereof.
  • a preferred soft elastic gelatin capsule has a composition comprising gelatin NF & EP (Type 195) (about 42.6% by weight), glycerin (USP) (about 96% active; about 13.2% by weight), purified water (USP) (about 27.4% by weight), sorbitol special (about 16% by weight) and titanium dioxide (USP) (about 0.4% by weight).
  • gelatin NF & EP Type 195
  • USP glycerin
  • USP purified water
  • USP sorbitol special
  • titanium dioxide titanium dioxide
  • Various methods can be used for manufacturing and filling the soft elastic gelatin capsules, for example, a seamless capsule method, a rotary method (developed by Scherer) or a method using a Liner ® machine or an Accogel ® machine, and the like. Also various manufacturing machines can be used for manufacturing the capsules.
  • Hard gelatin capsules are purchased from Capsugel, Greenwood, S.C. Capsules are filled Manually or by capsule filling machine. The target filling volume/weight depends on the potency of the filling solution in combination with the desired dosage strength.
  • Solid state nuclear magnetic resonance analysis of samples was conducted in the following manner.
  • a Bruker AMX-400 MHz instrument was used with the following parameters: CP- MAS (cross-polarized magic angle spinning); spectrometer frequency for 13C was 100.627952576 MHz; pulse sequence was cp2lev; contact time was 2.5 milliseconds; temperature was 27.0 oC; spin rate was 7000 Hz; relaxation delay was 6.000 sec; 1st pulse width was 3.8 microseconds; 2nd pulse width was 8.6 microseconds; acquisition time was 0.034 seconds; sweep width was 30303.0 Hz; 2000 scans.
  • CP- MAS cross-polarized magic angle spinning
  • spectrometer frequency for 13C was 100.627952576 MHz
  • pulse sequence was cp2lev
  • contact time was 2.5 milliseconds
  • temperature was 27.0 oC
  • spin rate was 7000 Hz
  • relaxation delay was 6.000 sec
  • 1st pulse width was 3.8 microseconds
  • 2nd pulse width was 8.6
  • FT mid infrared analysis of samples was conducted in the following manner. Samples were analyzed as neat, undiluted powders.
  • a Nicolet Magna System 750 FT-IR spectrometer with a Spectra-Tech InspectIR video microanalysis accessory and a Germanium attenuated total reflectance (Ge ATR) crystal was used with the following parameters: the source was infrared; the detector was MCT/A; the beamsplitter was KBr; sample spacing was 2.0000; digitizer bits was 20; mirror velocity was 1.8988; the aperture was 100.00; sample gain was 1.0; the high pass filter was 200.0000; the low pass filter was 20000,0000; the number of sample scans was 128; the collection length was 79.9 seconds; the resolution was 4.000; the number of scan points was 8480; the number of FFT points was 8192; the laser frequency was 15798.0 cm -1; the interferogram peak position was 4096; the apodization was triangular; the number of background scans was 128 and the background gain
  • Amorphous ritonavir (40.0 g) was dissolved in boiling anhydrous ethanol (100 mL). Upon allowing this solution to cool to room temperature, a saturated solution was obtained. After standing overnight at room temperature, the resulting solid was isolated from the mixture by filtration and was air dried to provide Form II (approximately 24.0 g).
  • Example 3a The crude, wet product of Example 3a was slurried in 1N HCl (192 mL) and the slurry was heated to 70°C with stirring. After 1 hour, THF (100 mL) was added and stirring at 65°C was continued for 4 hours. The mixture was then allowed to cool to 20-25°C and was stirred overnight at 20-25°C. The THF was removed by evaporation under vacuum and the resulting aqueous solution was cooled to about 5°C, causing some precipitation to occur. The aqueous mixture was adjusted to pH 7 by addition of 50% aqueous sodium hydroxide (about 18.3 g). The resulting mixture was extracted with ethyl acetate (2 x 100 mL) at about 15°C.
  • N-((N-Methyl-N((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (10.6 g, 33.9 mmol; U.S. Patent No. 5,539,122 and International Patent Application No. WO98/00410 ), the product of Example 3b (10.0 g, 32.2 mmol) and 1-hydroxybenzotriazole (5.2 g, 34 mmol) were dissolved in THF (200 mL). 1,3-dicylclohexylcarbodiimide (DCC, 7.0 g, 34 mmol) was then added to the THF mixture and the mixture was stirred at 22°C for 4 hours.
  • DCC 1,3-dicylclohexylcarbodiimide
  • Citric acid 25 mL of 10% aqueous solution was added and stirring continued for 30 minutes. The THF was then evaporated under vacuum. The residue was dissolved in ethyl acetate (250 mL) and washed with 10% citric acid solution (175 mL). NaCl (5 g) was added to accelerate the separation of the layers. The organic layer was sequentially washed with 10% aq. sodium carbonate (2 x 200 mL) and water (200 mL). The organic layer was then dried over sodium sulfate (20 g), filtered and evaporated under vacuum.
  • the ethanol/butylated hydroxytoluene is then added to the mixing tank, followed by the 118.0 g of ethanol measured previously, and mixed for at least 10 minutes.
  • 10 g of water is then charged into the tank and mixed until the solution is clear (for not less than 30 minutes).
  • the sides of the vessel are scraped for ritonavir, and mixed for not less than an additional 30 minutes.
  • 60.0 g of Polyoxyl 35 castor oil is charged into the tank and mixed until uniform.
  • the solution is stored at 2-8 °C until encapsulation.
  • 1.0 g of the solution is filled into each soft gelatin capsule (die: 18 oblong [18BE]; gel: 005L2DDXHB-EP; gel dyes: white 920P).
  • the soft gelatin capsules are then dried, and stored at 2-8 °C.
  • Dogs (beagle dogs, mixed sexes, weighing 7-14 kg) were fasted overnight prior to dosing, but were permitted water ad libitum. Each dog received a 100 ⁇ g/kg subcutaneous dose of histamine approximately 30 minutes prior to dosing. Each dog received a single dosage form corresponding to a 5 mg/kg dose of the drug. The dose was followed by approximately 10 milliliters of water. Blood samples were obtained from each animal prior to dosing and 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours after drug administration. The plasma was separated from the red cells by centrifugation and frozen (-30 °C) until analysis.
  • the invention provides a pharmaceutical composition comprising:
  • the HIV protease inhibiting compound is ritonavir or a combination of ritonavir and another HIV protease inhibiting compound.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • AIDS & HIV (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyrrole Compounds (AREA)
EP10177365.3A 2000-01-19 2000-12-01 Verbesserte pharmazeutische zusammensetzungen Revoked EP2269591B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI200031095T SI2269591T1 (en) 2000-01-19 2000-12-01 Improved pharmaceutical formulations

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US48773900A 2000-01-19 2000-01-19
EP00982360A EP1248600B1 (de) 2000-01-19 2000-12-01 Verbesserte pharmazeutische zusammensetzungen von hiv-proteasehemmern
EP07121429A EP1917958B1 (de) 2000-01-19 2000-12-01 Verbesserte pharmazeutische Formulierungen von HIV Protease Hemmern

Related Parent Applications (4)

Application Number Title Priority Date Filing Date
EP00982360.0 Division 2000-12-01
EP00982360A Division EP1248600B1 (de) 2000-01-19 2000-12-01 Verbesserte pharmazeutische zusammensetzungen von hiv-proteasehemmern
EP07121429A Division EP1917958B1 (de) 2000-01-19 2000-12-01 Verbesserte pharmazeutische Formulierungen von HIV Protease Hemmern
EP07121429.0 Division 2007-11-23

Publications (3)

Publication Number Publication Date
EP2269591A2 true EP2269591A2 (de) 2011-01-05
EP2269591A3 EP2269591A3 (de) 2011-07-27
EP2269591B1 EP2269591B1 (de) 2018-04-04

Family

ID=23936923

Family Applications (3)

Application Number Title Priority Date Filing Date
EP00982360A Revoked EP1248600B1 (de) 2000-01-19 2000-12-01 Verbesserte pharmazeutische zusammensetzungen von hiv-proteasehemmern
EP07121429A Revoked EP1917958B1 (de) 2000-01-19 2000-12-01 Verbesserte pharmazeutische Formulierungen von HIV Protease Hemmern
EP10177365.3A Revoked EP2269591B1 (de) 2000-01-19 2000-12-01 Verbesserte pharmazeutische zusammensetzungen

Family Applications Before (2)

Application Number Title Priority Date Filing Date
EP00982360A Revoked EP1248600B1 (de) 2000-01-19 2000-12-01 Verbesserte pharmazeutische zusammensetzungen von hiv-proteasehemmern
EP07121429A Revoked EP1917958B1 (de) 2000-01-19 2000-12-01 Verbesserte pharmazeutische Formulierungen von HIV Protease Hemmern

Country Status (26)

Country Link
EP (3) EP1248600B1 (de)
JP (1) JP4769400B2 (de)
KR (1) KR100861885B1 (de)
CN (1) CN100536833C (de)
AT (1) ATE395049T1 (de)
AU (2) AU1940501A (de)
BG (1) BG66112B1 (de)
BR (1) BR0011864A (de)
CA (1) CA2395987C (de)
CY (3) CY1108197T1 (de)
CZ (1) CZ304118B6 (de)
DE (1) DE60038899D1 (de)
DK (3) DK1917958T3 (de)
ES (3) ES2676151T3 (de)
HK (1) HK1120213A1 (de)
HU (1) HU229778B1 (de)
IL (2) IL150265A0 (de)
MX (1) MXPA02007097A (de)
NO (1) NO331400B1 (de)
NZ (1) NZ519724A (de)
PT (3) PT2269591T (de)
SI (3) SI1917958T1 (de)
SK (1) SK287143B6 (de)
TR (1) TR201809435T4 (de)
WO (1) WO2001052821A1 (de)
ZA (1) ZA200205109B (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2359945C (en) 1999-11-12 2011-04-26 Abbott Laboratories Inhibitors of crystallization in a solid dispersion
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
GB0615211D0 (en) * 2006-07-31 2006-09-06 Ge Healthcare Uk Ltd Asymmetric flouro-substituted polymethine dyes
WO2009019661A1 (en) * 2007-08-07 2009-02-12 Ranbaxy Laboratories Limited Process for preparation of amorphous lopinavir
US9096556B2 (en) 2011-05-27 2015-08-04 Hetero Research Foundation Amorphous ritonavir co-precipitated
GB201808564D0 (en) 2018-05-24 2018-07-11 Douglas Pharmaceuticals Ltd Treatments

Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008701A1 (en) 1990-11-19 1992-05-29 Monsanto Company Retroviral protease inhibitors
EP0490667A2 (de) 1990-12-11 1992-06-17 Japan Energy Corporation HIV-Proteaseinhibitoren
EP0532466A2 (de) 1991-09-12 1993-03-17 Ciba-Geigy Ag 5-Amino-4-Hydroxyhexansäurederivate als Therapeutika
US5196438A (en) 1989-12-11 1993-03-23 Hoffmann-La Roche Inc. Amino acid derivatives
WO1993007128A1 (en) 1991-10-11 1993-04-15 The Du Pont Merck Pharmaceutical Company Cyclic ureas and analogues useful as retroviral protease inhibitiors
EP0541168A1 (de) 1991-11-08 1993-05-12 Merck & Co. Inc. HIV-Protease-Inhibitoren verwendbar in der AIDS-Behandlung
EP0560268A1 (de) 1992-03-13 1993-09-15 Bio-Mega/Boehringer Ingelheim Research Inc. Substituierte Pipecoline-Säurederivate als HIV-Protease-Hemmer
WO1993023368A1 (en) 1992-05-20 1993-11-25 G.D. Searle & Co. Urea-containing hydroxyethylamine compounds as retroviral protease inhibitors
EP0580402A2 (de) 1992-07-20 1994-01-26 E.R. Squibb & Sons, Inc. Amindiole als Protease-Hemmer
WO1994005639A1 (en) 1992-09-08 1994-03-17 Vertex Pharmaceuticals Incorporated Sulfonamide inhibitors of hiv-aspartyl protease
WO1994014436A1 (en) 1992-12-29 1994-07-07 Abbott Laboratories Retroviral protease inhibiting compounds
WO1995006061A1 (en) 1993-08-20 1995-03-02 G.D. Searle & Co. Retroviral protease inhibitors and combinations thereof
WO1995009843A1 (en) 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Hiv protease inhibitors
US5413999A (en) 1991-11-08 1995-05-09 Merck & Co., Inc. HIV protease inhibitors useful for the treatment of AIDS
WO1995030670A2 (en) 1994-05-06 1995-11-16 Pharmacia & Upjohn Company Pyranone compounds useful to treat retroviral infections
US5484801A (en) 1994-01-28 1996-01-16 Abbott Laboratories Pharmaceutical composition for inhibiting HIV protease
US5539122A (en) 1989-05-23 1996-07-23 Abbott Laboratories Retroviral protease inhibiting compounds
US5559158A (en) 1993-10-01 1996-09-24 Abbott Laboratories Pharmaceutical composition
US5567823A (en) 1995-06-06 1996-10-22 Abbott Laboratories Process for the preparation of an HIV protease inhibiting compound
WO1997001349A1 (en) 1995-06-29 1997-01-16 Abbott Laboratories Use of ritonavir (abt-538) for improving the pharmacokinetics of drugs metabolized by cytochrome p450 in a method of treating aids
US5597926A (en) 1989-05-23 1997-01-28 Abbott Laboratories Retroviral protease inhibiting compounds
WO1997021685A1 (en) 1995-12-13 1997-06-19 Abbott Laboratories Retroviral protease inhibiting compounds
US5654466A (en) 1993-10-22 1997-08-05 Abbott Laboratories Process for the preparation of a disubstituted 2,5-diamino-3-hydroxyhexane
WO1998000410A1 (en) 1996-06-28 1998-01-08 Abbott Laboratories Process for the preparation of a disubstituted thiazole
US5725878A (en) 1993-09-13 1998-03-10 Abbott Laboratories Pharmaceutical composition comprising HIV protease inhibiting compounds
WO1998022106A1 (en) 1996-11-21 1998-05-28 Abbott Laboratories Pharmaceutical composition

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US594836A (en) * 1897-11-30 Corner-brace
CA2238977A1 (en) * 1995-12-13 1997-06-19 Abbott Laboratories Retroviral protease inhibiting compounds
KR100815412B1 (ko) * 1999-06-04 2008-03-20 아보트 러보러터리즈 개선된 약제학적 제형

Patent Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5635523A (en) 1989-05-23 1997-06-03 Abbott Laboratories Retroviral protease inhibiting compounds
US5539122A (en) 1989-05-23 1996-07-23 Abbott Laboratories Retroviral protease inhibiting compounds
US5541206A (en) 1989-05-23 1996-07-30 Abbott Laboratories Retroviral protease inhibiting compounds
US5674882A (en) 1989-05-23 1997-10-07 Abbott Laboratories Retroviral protease inhibiting compounds
US5597926A (en) 1989-05-23 1997-01-28 Abbott Laboratories Retroviral protease inhibiting compounds
US5196438A (en) 1989-12-11 1993-03-23 Hoffmann-La Roche Inc. Amino acid derivatives
WO1992008701A1 (en) 1990-11-19 1992-05-29 Monsanto Company Retroviral protease inhibitors
EP0490667A2 (de) 1990-12-11 1992-06-17 Japan Energy Corporation HIV-Proteaseinhibitoren
EP0532466A2 (de) 1991-09-12 1993-03-17 Ciba-Geigy Ag 5-Amino-4-Hydroxyhexansäurederivate als Therapeutika
WO1993007128A1 (en) 1991-10-11 1993-04-15 The Du Pont Merck Pharmaceutical Company Cyclic ureas and analogues useful as retroviral protease inhibitiors
US5413999A (en) 1991-11-08 1995-05-09 Merck & Co., Inc. HIV protease inhibitors useful for the treatment of AIDS
EP0541168A1 (de) 1991-11-08 1993-05-12 Merck & Co. Inc. HIV-Protease-Inhibitoren verwendbar in der AIDS-Behandlung
EP0560268A1 (de) 1992-03-13 1993-09-15 Bio-Mega/Boehringer Ingelheim Research Inc. Substituierte Pipecoline-Säurederivate als HIV-Protease-Hemmer
WO1993023368A1 (en) 1992-05-20 1993-11-25 G.D. Searle & Co. Urea-containing hydroxyethylamine compounds as retroviral protease inhibitors
EP0580402A2 (de) 1992-07-20 1994-01-26 E.R. Squibb & Sons, Inc. Amindiole als Protease-Hemmer
WO1994005639A1 (en) 1992-09-08 1994-03-17 Vertex Pharmaceuticals Incorporated Sulfonamide inhibitors of hiv-aspartyl protease
WO1994014436A1 (en) 1992-12-29 1994-07-07 Abbott Laboratories Retroviral protease inhibiting compounds
WO1995006061A1 (en) 1993-08-20 1995-03-02 G.D. Searle & Co. Retroviral protease inhibitors and combinations thereof
US5725878A (en) 1993-09-13 1998-03-10 Abbott Laboratories Pharmaceutical composition comprising HIV protease inhibiting compounds
US5559158A (en) 1993-10-01 1996-09-24 Abbott Laboratories Pharmaceutical composition
US5484926A (en) 1993-10-07 1996-01-16 Agouron Pharmaceuticals, Inc. HIV protease inhibitors
WO1995009843A1 (en) 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Hiv protease inhibitors
US5654466A (en) 1993-10-22 1997-08-05 Abbott Laboratories Process for the preparation of a disubstituted 2,5-diamino-3-hydroxyhexane
US5484801A (en) 1994-01-28 1996-01-16 Abbott Laboratories Pharmaceutical composition for inhibiting HIV protease
WO1995030670A2 (en) 1994-05-06 1995-11-16 Pharmacia & Upjohn Company Pyranone compounds useful to treat retroviral infections
US5852195A (en) 1994-05-06 1998-12-22 Pharmacia & Upjohn Company Pyranone compounds useful to treat retroviral infections
US5567823A (en) 1995-06-06 1996-10-22 Abbott Laboratories Process for the preparation of an HIV protease inhibiting compound
WO1997001349A1 (en) 1995-06-29 1997-01-16 Abbott Laboratories Use of ritonavir (abt-538) for improving the pharmacokinetics of drugs metabolized by cytochrome p450 in a method of treating aids
WO1997021685A1 (en) 1995-12-13 1997-06-19 Abbott Laboratories Retroviral protease inhibiting compounds
US5914332A (en) 1995-12-13 1999-06-22 Abbott Laboratories Retroviral protease inhibiting compounds
WO1998000410A1 (en) 1996-06-28 1998-01-08 Abbott Laboratories Process for the preparation of a disubstituted thiazole
WO1998022106A1 (en) 1996-11-21 1998-05-28 Abbott Laboratories Pharmaceutical composition

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
2ND NATIONAL CONFERENCE ON HUMAN RETROVIRUSES AND RELATED INFECTIONS, 22 January 1995 (1995-01-22)
CHEM. PHARM. BULL., vol. 40, no. 8, 1992, pages 2251
U.S. PHARMACOPEIA, 1995, pages 1843 - 1844

Also Published As

Publication number Publication date
CA2395987C (en) 2009-12-22
BG106976A (bg) 2003-05-30
IL150265A (en) 2015-02-26
EP1917958A3 (de) 2008-08-27
CY1112995T1 (el) 2016-04-13
PT1917958E (pt) 2012-08-16
CY1108197T1 (el) 2014-02-12
DK1917958T3 (da) 2012-09-24
EP1917958A2 (de) 2008-05-07
CY1120408T1 (el) 2019-07-10
AU1940501A (en) 2001-07-31
AU2006235895B2 (en) 2009-08-13
SI2269591T1 (en) 2018-08-31
CN100536833C (zh) 2009-09-09
ES2304990T3 (es) 2008-11-01
SI1917958T1 (sl) 2012-10-30
JP4769400B2 (ja) 2011-09-07
PT1248600E (pt) 2008-08-25
IL150265A0 (en) 2002-12-01
JP2003533435A (ja) 2003-11-11
SK11102002A3 (sk) 2002-12-03
CZ304118B6 (cs) 2013-11-06
HUP0302070A2 (hu) 2003-09-29
HU229778B1 (hu) 2014-07-28
CN1424907A (zh) 2003-06-18
EP1917958B1 (de) 2012-06-13
DK1248600T3 (da) 2008-09-08
ES2676151T3 (es) 2018-07-17
ATE395049T1 (de) 2008-05-15
HUP0302070A3 (en) 2007-02-28
ZA200205109B (en) 2003-10-31
CA2395987A1 (en) 2001-07-26
PT2269591T (pt) 2018-07-09
CZ20022663A3 (cs) 2002-11-13
NO331400B1 (no) 2011-12-19
HK1120213A1 (en) 2009-03-27
BG66112B1 (bg) 2011-05-31
WO2001052821A1 (en) 2001-07-26
KR100861885B1 (ko) 2008-10-09
SI1248600T1 (sl) 2008-08-31
KR20020082210A (ko) 2002-10-30
EP2269591A3 (de) 2011-07-27
AU2006235895A1 (en) 2006-11-30
NZ519724A (en) 2004-07-30
NO20023455D0 (no) 2002-07-18
SK287143B6 (sk) 2010-01-07
MXPA02007097A (es) 2003-01-28
NO20023455L (no) 2002-09-18
BR0011864A (pt) 2004-07-20
ES2387579T3 (es) 2012-09-26
DK2269591T3 (en) 2018-07-16
TR201809435T4 (tr) 2018-07-23
EP2269591B1 (de) 2018-04-04
DE60038899D1 (de) 2008-06-26
EP1248600A1 (de) 2002-10-16
PL361396A1 (en) 2004-10-04
EP1248600B1 (de) 2008-05-14

Similar Documents

Publication Publication Date Title
US7432294B2 (en) Pharmaceutical formulations
EP1733725B2 (de) Arzneimittellösung enthaltend Ritonavir, ein Lösungsmittel (langkettige Fettsäure) und Wasser
AU2006235895B2 (en) Improved pharmaceutical formulations

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AC Divisional application: reference to earlier application

Ref document number: 1917958

Country of ref document: EP

Kind code of ref document: P

Ref document number: 1248600

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: RO SI

RIN1 Information on inventor provided before grant (corrected)

Inventor name: ALANI, LAMAN

Inventor name: GHOSH, SOUMOJEET

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: RO SI

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1151471

Country of ref document: HK

17P Request for examination filed

Effective date: 20120523

17Q First examination report despatched

Effective date: 20130128

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ABBVIE INC.

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIN1 Information on inventor provided before grant (corrected)

Inventor name: GHOSH, SOUMOJEET

Inventor name: ALANI, LAMAN

INTG Intention to grant announced

Effective date: 20171024

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AC Divisional application: reference to earlier application

Ref document number: 1917958

Country of ref document: EP

Kind code of ref document: P

Ref document number: 1248600

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: RO SI

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 984820

Country of ref document: AT

Kind code of ref document: T

Effective date: 20180415

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 60049801

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Ref document number: 2269591

Country of ref document: PT

Date of ref document: 20180709

Kind code of ref document: T

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20180703

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20180713

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2676151

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20180717

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 60049801

Country of ref document: DE

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20180401863

Country of ref document: GR

Effective date: 20190109

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

26N No opposition filed

Effective date: 20190107

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20190918

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20191127

Year of fee payment: 20

Ref country code: PT

Payment date: 20191127

Year of fee payment: 20

Ref country code: IE

Payment date: 20191125

Year of fee payment: 20

Ref country code: FI

Payment date: 20191125

Year of fee payment: 20

Ref country code: DE

Payment date: 20191114

Year of fee payment: 20

Ref country code: MC

Payment date: 20191127

Year of fee payment: 20

Ref country code: SE

Payment date: 20191209

Year of fee payment: 20

Ref country code: CY

Payment date: 20191101

Year of fee payment: 20

REG Reference to a national code

Ref country code: AT

Ref legal event code: UEP

Ref document number: 984820

Country of ref document: AT

Kind code of ref document: T

Effective date: 20180404

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20191125

Year of fee payment: 20

Ref country code: IT

Payment date: 20191219

Year of fee payment: 20

Ref country code: FR

Payment date: 20191122

Year of fee payment: 20

Ref country code: GR

Payment date: 20191125

Year of fee payment: 20

Ref country code: BE

Payment date: 20191119

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R061

Ref document number: 60049801

Country of ref document: DE

PLBR Kind of request for revocation recorded

Free format text: ORIGINAL CODE: EPIDOSNRVR2

PLBT Request for revocation filed by patent holder

Free format text: ORIGINAL CODE: EPIDOSNRVR1

PLDH Decision on request for revocation

Free format text: ORIGINAL CODE: EPIDOSNRVR3

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20191125

Year of fee payment: 20

Ref country code: TR

Payment date: 20191126

Year of fee payment: 20

Ref country code: CH

Payment date: 20191028

Year of fee payment: 20

RDAA Patent revoked on request of proprietor

Free format text: ORIGINAL CODE: 0009220

PLBU Request for revocation filed by patent holder

Free format text: ORIGINAL CODE: EPIDOSNRVR6

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: PATENT REVOKED BY PROPRIETOR

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20191126

Year of fee payment: 20

Ref country code: ES

Payment date: 20200102

Year of fee payment: 20

RVAA Request for revocation filed after opposition period found admissible

Filing date: 20200325

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 60049801

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: MK

Effective date: 20201130

REG Reference to a national code

Ref country code: DK

Ref legal event code: EUP

Expiry date: 20201201

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20201130

Ref country code: IE

Ref legal event code: MK9A

REG Reference to a national code

Ref country code: FI

Ref legal event code: MAE

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK07

Ref document number: 984820

Country of ref document: AT

Kind code of ref document: T

Effective date: 20201201

REG Reference to a national code

Ref country code: BE

Ref legal event code: MK

Effective date: 20201201

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20220128